Pub Date : 2024-07-29DOI: 10.1101/2024.07.29.24311157
N. Holt, C. L. Smith, C. X. Gao, B. Borg, T. J. Lane, D. Brown, J. Ikin, A. Makar, T. McCrabb, M. Thomas, K. Nilsen, B. Thompson, M. Abramson
Background and objective: The 2014 Hazelwood coalmine fire exposed residents in nearby Morwell to high concentrations of particulate matter <2.5 m (PM2.5) for approximately 6 weeks. This analysis aimed to evaluate the long-term impact on respiratory health. Methods: Adults from Morwell and the unexposed town of Sale completed validated respiratory questionnaires and performed spirometry, gas transfer and oscillometry 3.5-4 years (Round 1) and 7.3-7.8 years (Round 2) after the fire. Individual PM2.5 exposure levels were estimated using chemical transport models mapped onto participant-reported time-location data. Mixed-effects regression models were fitted to analyse associations between PM2.5 exposure and outcomes, controlling for key confounders. Results: From 519 (346 exposed) Round 1 participants, 329 (217 exposed) participated in Round 2. Spirometry and gas transfer in Round 2 were mostly lower compared with Round 1, excepting FVC (increased) and FEV1 (minimal change). The effect of mine fire-related PM2.5 exposure changed from a negative effect in Round 1 to no effect in Round 2 for both pre- (p=0.005) and post-bronchodilator FVC (p=0.032). PM2.5 was not associated with gas transfer in either round. For post-bronchodilator reactance and area under the curve, a negative impact of PM2.5 in Round 1 showed signs of recovery in Round 2 (both p<0.001). Conclusion: In this novel study evaluating long-term respiratory outcomes after medium-duration high concentration PM2.5 exposure, the attenuated associations between exposure and respiratory function may indicate some recovery in lung function. With increased frequency and severity of landscape fires observed globally, these results inform public health policies and planning.
{"title":"Lung function may recover after exposure to smoke from a coal mine fire: cohort study","authors":"N. Holt, C. L. Smith, C. X. Gao, B. Borg, T. J. Lane, D. Brown, J. Ikin, A. Makar, T. McCrabb, M. Thomas, K. Nilsen, B. Thompson, M. Abramson","doi":"10.1101/2024.07.29.24311157","DOIUrl":"https://doi.org/10.1101/2024.07.29.24311157","url":null,"abstract":"Background and objective: The 2014 Hazelwood coalmine fire exposed residents in nearby Morwell to high concentrations of particulate matter <2.5 m (PM2.5) for approximately 6 weeks. This analysis aimed to evaluate the long-term impact on respiratory health. Methods: Adults from Morwell and the unexposed town of Sale completed validated respiratory questionnaires and performed spirometry, gas transfer and oscillometry 3.5-4 years (Round 1) and 7.3-7.8 years (Round 2) after the fire. Individual PM2.5 exposure levels were estimated using chemical transport models mapped onto participant-reported time-location data. Mixed-effects regression models were fitted to analyse associations between PM2.5 exposure and outcomes, controlling for key confounders. Results: From 519 (346 exposed) Round 1 participants, 329 (217 exposed) participated in Round 2. Spirometry and gas transfer in Round 2 were mostly lower compared with Round 1, excepting FVC (increased) and FEV1 (minimal change). The effect of mine fire-related PM2.5 exposure changed from a negative effect in Round 1 to no effect in Round 2 for both pre- (p=0.005) and post-bronchodilator FVC (p=0.032). PM2.5 was not associated with gas transfer in either round. For post-bronchodilator reactance and area under the curve, a negative impact of PM2.5 in Round 1 showed signs of recovery in Round 2 (both p<0.001). Conclusion: In this novel study evaluating long-term respiratory outcomes after medium-duration high concentration PM2.5 exposure, the attenuated associations between exposure and respiratory function may indicate some recovery in lung function. With increased frequency and severity of landscape fires observed globally, these results inform public health policies and planning.","PeriodicalId":506788,"journal":{"name":"medRxiv","volume":"1 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141796747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-29DOI: 10.1101/2024.07.28.24311145
J. Harbison, J. McCormack, O. Brych, R. Collins, N. O’Connell, P. J. Kelly, T. Cassidy
Atrial Fibrillation (AF) has been Identified as the single largest cause of ischaemic stroke in the Irish population. Previous research showed that widespread adoption of Direct Oral Anticoagulant (DOAC) prophylaxis had not been associated with a reduction in AF associated stroke prevalence. The Irish National Audit of Stroke (INAS) undertook a more detailed study to determine the characteristics of anticoagulation practice in AF associated stroke particularly adherence to prescribing guidelines and effect on thrombolysis rate. Methods: Data from INAS were analysed for the period 2017-2022 inclusive. An enhanced dataset with additional questions about adherence with prescription and International Normalized Ratio (INR) control was collected for 2022 was also considered separately. Results. Complete AF Data were available on 22485 of 26829 incidents admitted over this period. Of these, 19260 (85.6%) were ischaemic strokes, mean age was 71.8 and 57.1% were male. In 5321 of these cases, the AF was identified and in 2835 (53.3%) recognized before the stroke and 2281 (80.4%) had been prescribed anticoagulation. The population with previously unknown AF were significantly younger on average than those on anticoagulation (76.8 years vs. 79.1 years (p<0.0001, t-test)), Group C; 78.8 years (p<0.0001), they were also much more likely to have received thrombolysis (17.3 % vs. 4.0% (Chi Sq, p<0.0001)). There were 4999 stroke in 2022, 4272 (85.4%) were ischemic and 1270 (29.7%) of these were AF associated. Of the 660 total strokes, 597 (90.5%) anticoagulated at presentation were receiving DOACs, of which 557 were ischaemic. Forty-eight (9.5%) had their anticoagulation paused and 40 admitted to poor compliance (7.9%). Conclusion. Nearly half of people with AF detected after stroke was previously unknown. Those with known AF were mainly appropriately treated with DOACs and constitute breakthrough strokes. Subjects receiving DOACs were much less likely to receive thrombolytic therapy even than those taking Warfarin.
{"title":"Anticoagulation Usage and Thrombolytic Therapy in Subjects with Atrial Fibrillation Associated Ischaemic Stroke.","authors":"J. Harbison, J. McCormack, O. Brych, R. Collins, N. O’Connell, P. J. Kelly, T. Cassidy","doi":"10.1101/2024.07.28.24311145","DOIUrl":"https://doi.org/10.1101/2024.07.28.24311145","url":null,"abstract":"Atrial Fibrillation (AF) has been Identified as the single largest cause of ischaemic stroke in the Irish population. Previous research showed that widespread adoption of Direct Oral Anticoagulant (DOAC) prophylaxis had not been associated with a reduction in AF associated stroke prevalence. The Irish National Audit of Stroke (INAS) undertook a more detailed study to determine the characteristics of anticoagulation practice in AF associated stroke particularly adherence to prescribing guidelines and effect on thrombolysis rate. Methods: Data from INAS were analysed for the period 2017-2022 inclusive. An enhanced dataset with additional questions about adherence with prescription and International Normalized Ratio (INR) control was collected for 2022 was also considered separately. Results. Complete AF Data were available on 22485 of 26829 incidents admitted over this period. Of these, 19260 (85.6%) were ischaemic strokes, mean age was 71.8 and 57.1% were male. In 5321 of these cases, the AF was identified and in 2835 (53.3%) recognized before the stroke and 2281 (80.4%) had been prescribed anticoagulation. The population with previously unknown AF were significantly younger on average than those on anticoagulation (76.8 years vs. 79.1 years (p<0.0001, t-test)), Group C; 78.8 years (p<0.0001), they were also much more likely to have received thrombolysis (17.3 % vs. 4.0% (Chi Sq, p<0.0001)). There were 4999 stroke in 2022, 4272 (85.4%) were ischemic and 1270 (29.7%) of these were AF associated. Of the 660 total strokes, 597 (90.5%) anticoagulated at presentation were receiving DOACs, of which 557 were ischaemic. Forty-eight (9.5%) had their anticoagulation paused and 40 admitted to poor compliance (7.9%). Conclusion. Nearly half of people with AF detected after stroke was previously unknown. Those with known AF were mainly appropriately treated with DOACs and constitute breakthrough strokes. Subjects receiving DOACs were much less likely to receive thrombolytic therapy even than those taking Warfarin.","PeriodicalId":506788,"journal":{"name":"medRxiv","volume":"27 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141796759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-29DOI: 10.1101/2024.07.29.24311063
V. Larios-Serrato, Hilda A. Valdez-Salazar, Javier Torres, M. Camorlinga-Ponce, P. Piña-Sánchez, Fernando Minauro-Sanmiguel, M. Ruiz-Tachiquín, Dr Martha-Eugenia Ruiz-Tachiquín, Av, Cuauhtémoc, Colonia
Worldwide, gastric cancer (GC) is a common malignancy with the highest mortality rate among digestive system diseases. The present study of GC and loss of heterozygosity (LOH) is relevant to understanding tumor biology and establishing essential aspects of cancer. Here, DNA samples from Mexican patients with diffuse GC (DGC), intestinal GC (IGC), or non-atrophic gastritis (NAG; control) were purified, and whole-genome high-density arrays were performed. Posteriorly, LOH was identified among the tissue samples, and cancer genes and signaling pathways were analyzed to determine the most altered. Detailed bioinformatics analysis was developed to associate LOH with the Hallmarks of Cancer according to their frequency in patient samples, participation in metabolic pathways, network interactions, and enrichment of Cancer Hallmark genes. LOH-genes in GC were PTPR, NDUFS3, PAK3, IRAK1, IKBKG, TKTL1, PRPS1, GNAI2, RHOA, MAPKA, and MST1R. Genes that stand out at NAG involve proliferation and growth; those at IGC trigger genomic instability, tissue invasion, metastasis, and arrest of cell death; and those at DGC involve energy metabolism, the destruction of immune evasion, and replicative immortality. Other events, such as sustained angiogenesis, were similar between NAG-IGC-DGC. Together, these are molecular, cellular, and metabolic events that must be monitored in GC patients. Our findings must be validated to develop molecular tests for diagnosis, prognosis, treatment response, and, most importantly, screening tests.
{"title":"Loss of heterozygosity in gastric cancers in a set of Mexican patients","authors":"V. Larios-Serrato, Hilda A. Valdez-Salazar, Javier Torres, M. Camorlinga-Ponce, P. Piña-Sánchez, Fernando Minauro-Sanmiguel, M. Ruiz-Tachiquín, Dr Martha-Eugenia Ruiz-Tachiquín, Av, Cuauhtémoc, Colonia","doi":"10.1101/2024.07.29.24311063","DOIUrl":"https://doi.org/10.1101/2024.07.29.24311063","url":null,"abstract":"Worldwide, gastric cancer (GC) is a common malignancy with the highest mortality rate among digestive system diseases. The present study of GC and loss of heterozygosity (LOH) is relevant to understanding tumor biology and establishing essential aspects of cancer. Here, DNA samples from Mexican patients with diffuse GC (DGC), intestinal GC (IGC), or non-atrophic gastritis (NAG; control) were purified, and whole-genome high-density arrays were performed. Posteriorly, LOH was identified among the tissue samples, and cancer genes and signaling pathways were analyzed to determine the most altered. Detailed bioinformatics analysis was developed to associate LOH with the Hallmarks of Cancer according to their frequency in patient samples, participation in metabolic pathways, network interactions, and enrichment of Cancer Hallmark genes. LOH-genes in GC were PTPR, NDUFS3, PAK3, IRAK1, IKBKG, TKTL1, PRPS1, GNAI2, RHOA, MAPKA, and MST1R. Genes that stand out at NAG involve proliferation and growth; those at IGC trigger genomic instability, tissue invasion, metastasis, and arrest of cell death; and those at DGC involve energy metabolism, the destruction of immune evasion, and replicative immortality. Other events, such as sustained angiogenesis, were similar between NAG-IGC-DGC. Together, these are molecular, cellular, and metabolic events that must be monitored in GC patients. Our findings must be validated to develop molecular tests for diagnosis, prognosis, treatment response, and, most importantly, screening tests.","PeriodicalId":506788,"journal":{"name":"medRxiv","volume":"26 4-5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141796763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-29DOI: 10.1101/2024.07.29.24311153
T. Jordanek, M. Lamos, R. Mareček
The analysis of EEG microstates is a useful method for exploring large-scale networks and brain dynamics. In addition to the often-reported microstates, or so-called 'canonical microstates', another topography has been reported in the literature - topography with a prominent straight line separating positive and negative values that extends from the nasion to the inion (vertical topography - VT). This topography was also revealed in our simultaneous EEG/fMRI and shielded cabin EEG data collected from 77 participants. Following analyses based on human and phantom data, we conclude that VT partially reflects artifacts caused by unspecified movements of the EEG cap and its metallic components. Our conclusion is supported by evaluation of spatiotemporal characteristics of VT estimated from EEG acquired under various conditions, especially by significant correlation between the framewise displacement (obtained from human EEG/fMRI) and the temporal characteristics of VT. We recommend cautious interpretation of VT when revealed in the data. Its very presence as a resulting topography may affect the spatiotemporal parameters of the other microstates and distorts the shapes of the other topographies.
{"title":"Vertical topography in EEG microstates: Physiology or artifact manifestation?","authors":"T. Jordanek, M. Lamos, R. Mareček","doi":"10.1101/2024.07.29.24311153","DOIUrl":"https://doi.org/10.1101/2024.07.29.24311153","url":null,"abstract":"The analysis of EEG microstates is a useful method for exploring large-scale networks and brain dynamics. In addition to the often-reported microstates, or so-called 'canonical microstates', another topography has been reported in the literature - topography with a prominent straight line separating positive and negative values that extends from the nasion to the inion (vertical topography - VT). This topography was also revealed in our simultaneous EEG/fMRI and shielded cabin EEG data collected from 77 participants. Following analyses based on human and phantom data, we conclude that VT partially reflects artifacts caused by unspecified movements of the EEG cap and its metallic components. Our conclusion is supported by evaluation of spatiotemporal characteristics of VT estimated from EEG acquired under various conditions, especially by significant correlation between the framewise displacement (obtained from human EEG/fMRI) and the temporal characteristics of VT. We recommend cautious interpretation of VT when revealed in the data. Its very presence as a resulting topography may affect the spatiotemporal parameters of the other microstates and distorts the shapes of the other topographies.","PeriodicalId":506788,"journal":{"name":"medRxiv","volume":"5 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141796397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-29DOI: 10.1101/2024.07.27.24311110
E. T. Monson, S. M. Colbert, O. A. Andreassen, O. O. Ayinde, C. A. Bejan, Z. Ceja, H. Coon, E. DiBlasi, A. Izotova, E. A. Kaufman, M. Koromina, W. Myung, J. I. Nurnberger, A. Serretti, J. Smoller, M. Stein, C. C. Zai, Suicide Working Group of the Psychiatric Genomics , M. Aslan, P. B. Barr, T. Bigdeli, P. D. Harvey, N. Kimbrel, P. R. Patel, Cooperative Studies Program 572, D. Ruderfer, A. R. Docherty, N. Mullins, J. J. Mann
Background: Standardized definitions of suicidality phenotypes, including suicidal ideation (SI), attempt (SA), and death (SD) are a critical step towards improving understanding and comparison of results in suicide research. The complexity of suicidality contributes to heterogeneity in phenotype definitions, impeding evaluation of clinical and genetic risk factors across studies and efforts to combine samples within consortia. Here, we present expert and data-supported recommendations for defining suicidality and control phenotypes to facilitate merging current/legacy samples with definition variability and aid future sample creation. Methods: A subgroup of clinician researchers and experts from the Suicide Workgroup of the Psychiatric Genomics Consortium (PGC) reviewed existing PGC definitions for SI, SA, SD, and control groups and generated preliminary consensus guidelines for instrument-derived and international classification of disease (ICD) data. ICD lists were validated in two independent datasets (N = 9,151 and 12,394). Results: Recommendations are provided for evaluated instruments for SA and SI, emphasizing selection of lifetime measures phenotype-specific wording. Recommendations are also provided for defining SI and SD from ICD data. As the SA ICD definition is complex, SA code list recommendations were validated against instrument results with sensitivity (range = 15.4% to 80.6%), specificity (range = 67.6% to 97.4%), and positive predictive values (range = 0.59-0.93) reported. Conclusions: Best-practice guidelines are presented for the use of existing information to define SI/SA/SD in consortia research. These proposed definitions are expected to facilitate more homogeneous data aggregation for genetic and multisite studies. Future research should involve refinement, improved generalizability, and validation in diverse populations.
背景：自杀表型（包括自杀意念（SI）、自杀未遂（SA）和自杀死亡（SD））的标准化定义是提高自杀研究结果的理解和比较的关键一步。自杀倾向的复杂性导致了表型定义的异质性，阻碍了对不同研究的临床和遗传风险因素的评估，也阻碍了在联合体内合并样本的努力。在此，我们提出了专家建议和有数据支持的建议，用于定义自杀性和控制表型，以促进合并当前/传统样本中的定义差异，并帮助未来样本的创建。方法：来自精神疾病基因组学联盟（PGC）自杀问题工作组的临床研究人员和专家组成了一个分组，该分组对现有的 PGC 关于 SI、SA、SD 和对照组的定义进行了审查，并针对仪器得出的数据和国际疾病分类（ICD）数据提出了初步的共识指南。两个独立数据集（N = 9,151 和 12,394）对 ICD 列表进行了验证。结果：为 SA 和 SI 的评估工具提供了建议，强调选择终身测量表型特定的措辞。此外，还提供了根据 ICD 数据定义 SI 和 SD 的建议。由于 SA ICD 定义复杂，SA 代码表建议与工具结果进行了验证，报告了灵敏度（范围 = 15.4% 至 80.6%）、特异性（范围 = 67.6% 至 97.4%）和阳性预测值（范围 = 0.59-0.93）。结论：本文提出了在联合研究中使用现有信息定义 SI/SA/SD 的最佳实践指南。这些建议的定义有望促进基因研究和多地点研究的数据汇总更加统一。未来的研究应包括改进、提高通用性以及在不同人群中进行验证。
{"title":"Defining Suicidal Thought and Behavior Phenotypes for Genetic Studies","authors":"E. T. Monson, S. M. Colbert, O. A. Andreassen, O. O. Ayinde, C. A. Bejan, Z. Ceja, H. Coon, E. DiBlasi, A. Izotova, E. A. Kaufman, M. Koromina, W. Myung, J. I. Nurnberger, A. Serretti, J. Smoller, M. Stein, C. C. Zai, Suicide Working Group of the Psychiatric Genomics , M. Aslan, P. B. Barr, T. Bigdeli, P. D. Harvey, N. Kimbrel, P. R. Patel, Cooperative Studies Program 572, D. Ruderfer, A. R. Docherty, N. Mullins, J. J. Mann","doi":"10.1101/2024.07.27.24311110","DOIUrl":"https://doi.org/10.1101/2024.07.27.24311110","url":null,"abstract":"Background: Standardized definitions of suicidality phenotypes, including suicidal ideation (SI), attempt (SA), and death (SD) are a critical step towards improving understanding and comparison of results in suicide research. The complexity of suicidality contributes to heterogeneity in phenotype definitions, impeding evaluation of clinical and genetic risk factors across studies and efforts to combine samples within consortia. Here, we present expert and data-supported recommendations for defining suicidality and control phenotypes to facilitate merging current/legacy samples with definition variability and aid future sample creation. Methods: A subgroup of clinician researchers and experts from the Suicide Workgroup of the Psychiatric Genomics Consortium (PGC) reviewed existing PGC definitions for SI, SA, SD, and control groups and generated preliminary consensus guidelines for instrument-derived and international classification of disease (ICD) data. ICD lists were validated in two independent datasets (N = 9,151 and 12,394). Results: Recommendations are provided for evaluated instruments for SA and SI, emphasizing selection of lifetime measures phenotype-specific wording. Recommendations are also provided for defining SI and SD from ICD data. As the SA ICD definition is complex, SA code list recommendations were validated against instrument results with sensitivity (range = 15.4% to 80.6%), specificity (range = 67.6% to 97.4%), and positive predictive values (range = 0.59-0.93) reported. Conclusions: Best-practice guidelines are presented for the use of existing information to define SI/SA/SD in consortia research. These proposed definitions are expected to facilitate more homogeneous data aggregation for genetic and multisite studies. Future research should involve refinement, improved generalizability, and validation in diverse populations.","PeriodicalId":506788,"journal":{"name":"medRxiv","volume":"22 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141796616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Growing evidence indicates a significant correlation between the gut microbiota, immune system, and psychiatric disorders. Nevertheless, the impacts and interactions of the gut microbiota and immunophenotypes on psychiatric disorders remain unclear. Methods: We utilized a bidirectional Mendelian randomization (MR) study to evaluate the causal associations among the gut microbiota, immunophenotypes, and psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), posttraumatic stress disorder (PTSD), schizophrenia (SCZ), and Tourette's syndrome (TS). The primary analysis was conducted using the inverse variance weighted (IVW) method, with several complementary sensitivity analyses being performed to ensure the reliability of the results. Results: Our study reveals significant causal relationships between 22 immunophenotypes, 15 types of gut microbiota, and various psychiatric disorders. We further sought to ascertain whether immunophenotypes act as intermediaries in the pathway from gut microbiota to psychiatric disorders. In particular, three immunophenotypes were identified that mediate the causal effects of different gut microbiota on ADHD. Additionally, one immunophenotype was detected to mediate the causal effects of gut microbiota on PTSD. Conclusions: Our study indicates that immunophenotypes partially mediate the pathway from the gut microbiota to psychiatric disorders.
{"title":"Causal effect of the gut microbiota on the risk of psychiatric disorders and the mediating role of immunophenotypes","authors":"Zhisheng Hong, Ao He, Guanglong Huang, Xiaofeng Chen, Xiaoyu Wang, Xiaoyang Li, Hailun Chen, Xinqi Zhao, Ying Xu, Yangheng Xu, Ouyang Pei, Hai Wang, Jiapeng Deng, Pengyu Chen, Xian Zhang, Songtao Qi, Yaomin Li","doi":"10.1101/2024.07.29.24311128","DOIUrl":"https://doi.org/10.1101/2024.07.29.24311128","url":null,"abstract":"Background: Growing evidence indicates a significant correlation between the gut microbiota, immune system, and psychiatric disorders. Nevertheless, the impacts and interactions of the gut microbiota and immunophenotypes on psychiatric disorders remain unclear. Methods: We utilized a bidirectional Mendelian randomization (MR) study to evaluate the causal associations among the gut microbiota, immunophenotypes, and psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), posttraumatic stress disorder (PTSD), schizophrenia (SCZ), and Tourette's syndrome (TS). The primary analysis was conducted using the inverse variance weighted (IVW) method, with several complementary sensitivity analyses being performed to ensure the reliability of the results. Results: Our study reveals significant causal relationships between 22 immunophenotypes, 15 types of gut microbiota, and various psychiatric disorders. We further sought to ascertain whether immunophenotypes act as intermediaries in the pathway from gut microbiota to psychiatric disorders. In particular, three immunophenotypes were identified that mediate the causal effects of different gut microbiota on ADHD. Additionally, one immunophenotype was detected to mediate the causal effects of gut microbiota on PTSD. Conclusions: Our study indicates that immunophenotypes partially mediate the pathway from the gut microbiota to psychiatric disorders.","PeriodicalId":506788,"journal":{"name":"medRxiv","volume":"7 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141796514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-29DOI: 10.1101/2024.07.29.24311165
F. brindisino, A. Poser, D. Feller, D. Venturin
Frozen shoulder (FS) is a debilitating condition affecting the glenohumeral joint. As FS frequently manifests as a chronic condition, it intensifies pain and leads to disability and to a deterioration in overall quality of life, affecting physical, behavioral, mental, and social dimensions. While the impact of pain on disability is widely acknowledged, recent literature highlights a growing body of evidence indicating the correlation between pain and health-related, social, and mental distress and unfavorable outcomes in patients with FS. Up to day, the need for pain to be avoided or alleviated as much as possible has been challenged, with a paradigm shift from traditional biomedical models of pain towards a biopsychosocial model of pain disorders. Research has further shown that psychological factors might affect the function and quality of life in patients with pain and can modulate the individuals pain experience and therefore may play a role in the development and/or maintenance of chronic pain states. As the current healthcare pathway for subjects suffering from FS often inadequately addresses these healthcare needs, and professionals tend to predominantly concentrate on biological and clinical symptoms, the aim of this study will be to explore correlations among Patient-Reported Outcome Measures (PROMs) for pain, and disability, health-related domains, and ROM measurements in individuals with FS during their initial physiotherapy consultation.
肩周炎（FS）是一种影响盂肱关节的衰弱性疾病。由于肩周炎经常表现为慢性病，它加剧了疼痛，导致残疾和整体生活质量的下降，影响身体、行为、精神和社会等方面。尽管疼痛对残疾的影响已得到广泛承认，但最近的文献强调，越来越多的证据表明，FS 患者的疼痛与健康相关、社会和精神痛苦以及不良后果之间存在关联。时至今日，尽可能避免或减轻疼痛的需求已受到挑战，疼痛的范式已从传统的生物医学模式转向生物心理社会模式。研究进一步表明，心理因素可能会影响疼痛患者的功能和生活质量，并能调节个人的疼痛体验，因此可能在慢性疼痛状态的发展和/或维持中发挥作用。由于目前针对 FS 患者的医疗保健途径往往不能充分满足这些医疗保健需求，专业人员往往主要关注生物和临床症状，因此本研究旨在探讨 FS 患者在初次物理治疗咨询期间的疼痛、残疾、健康相关领域和 ROM 测量的 "患者报告结果测量"（PROMs）之间的相关性。
{"title":"Baseline correlation between pain, range of motion, disability, and health-related quality of life variables in subjects with frozen shoulder: A cross-sectional study","authors":"F. brindisino, A. Poser, D. Feller, D. Venturin","doi":"10.1101/2024.07.29.24311165","DOIUrl":"https://doi.org/10.1101/2024.07.29.24311165","url":null,"abstract":"Frozen shoulder (FS) is a debilitating condition affecting the glenohumeral joint. As FS frequently manifests as a chronic condition, it intensifies pain and leads to disability and to a deterioration in overall quality of life, affecting physical, behavioral, mental, and social dimensions. While the impact of pain on disability is widely acknowledged, recent literature highlights a growing body of evidence indicating the correlation between pain and health-related, social, and mental distress and unfavorable outcomes in patients with FS. Up to day, the need for pain to be avoided or alleviated as much as possible has been challenged, with a paradigm shift from traditional biomedical models of pain towards a biopsychosocial model of pain disorders. Research has further shown that psychological factors might affect the function and quality of life in patients with pain and can modulate the individuals pain experience and therefore may play a role in the development and/or maintenance of chronic pain states. As the current healthcare pathway for subjects suffering from FS often inadequately addresses these healthcare needs, and professionals tend to predominantly concentrate on biological and clinical symptoms, the aim of this study will be to explore correlations among Patient-Reported Outcome Measures (PROMs) for pain, and disability, health-related domains, and ROM measurements in individuals with FS during their initial physiotherapy consultation.","PeriodicalId":506788,"journal":{"name":"medRxiv","volume":"6 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141796524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-29DOI: 10.1101/2024.07.27.24311111
F. Xie, M. Jin, T. Ma, X. Zhou, S. Wang
Introduction During gastrointestinal endoscopy (GIE) procedures(upper/lower) performed under deep sedation, patients with coronary artery disease(CAD) have poorer tolerance, with higher incidence of hypotension and myocardial ischemia. Patients with CAD should particularly avoid hypoxemia caused by deep sedation and increased oxygen consumption caused by inadequate sedation. Recent data indicate that high-flow nasal oxygen therapy (HFNO) is recommended for preventing hypoxemia in high-risk patients. The data on cardiac cycle efficiency (CCE) from MostCare can be used to assess myocardial oxygen supply-demand balance in patients with CAD. HFNO may potentially improve myocardial oxygen supply during GIE under deep sedation. We hypothesize that compared to standard oxygen therapy (SOT), HFNO could improve CCE in patients with CAD. Methods and analysis The MEHIS (MostCare-Based Assessment of CCE in CAD PatientsHFNO versus SOT for GIE with sedation. The prospective single-center randomised controlled) study is a single-center randomized controlled trial comparing the effects of HFNO and SOT during GIE under deep sedation administered by anaesthesiologists in the procedure room in patients with CAD. Ninety patients will be randomly allocated in a 1:1 ratio to two parallel groups. The primary outcome is the difference in CCE levels between the two groups during sedation. Secondary outcomes are the incidence of hypotension(hypotension defined as a systolic blood pressure below 80 mmHg), values of BNP (brain natriuretic peptide), TnI (troponin I), and lactate levels at 6-12 hours post-operationthe occurrence of hypoxemia defined as SpO2 measurement equal to or below 92%, MostCare hemodynamic parameters excluding the primary outcome, interventions required to maintain upper airway patency, patient agitation episodes (assessed by touching the oxygen supply device), and presence of intraoperative adverse memories postoperatively. Keywords high-flow nasal oxygen therapy (HFNO); cardiac cycle efficiency (CCE); gastrointestinal endoscopy (GIE); coronary artery disease(CAD) Trial registration number ChiCTR2400086887 Strengths and limitations of this study 1. This is the first pragmatic randomized single-center study comparing HFNO to SOT for oxygenating patients with CAD undergoing GIE. 2. In contrast to comparing HFNO with high fraction of inspired oxygen (FiO2) typically used in SOT with low oxygen flow and consequently lower FiO2, this study adjusts gas flows to target roughly the same level of applied FiO2 in both groups. This approach aims to assess whether HFNO can improve CCE through positive end-expiratory pressure and/or dead space washout effects. 3. In SOT group, precise FiO2 cannot be guaranteed. That is why we utilized a pre-existing abacus to achieve the best equivalence. 4. Technically, blinding of practitioners and other nursing staff to the study groups is not feasible. However, the printout of recorded primary outcome measures is produced, allo
导言：在深度镇静下进行胃肠道内窥镜检查（上/下）时，冠状动脉疾病（CAD）患者的耐受性较差，低血压和心肌缺血的发生率较高。患有冠状动脉疾病的患者尤其要避免深度镇静导致的低氧血症和镇静不足导致的耗氧量增加。最近的数据表明，建议使用高流量鼻氧疗法（HFNO）来预防高危患者的低氧血症。来自 MostCare 的心脏循环效率（CCE）数据可用于评估 CAD 患者的心肌氧供需平衡。在深度镇静状态下进行 GIE 时，高频硝化氧有可能改善心肌供氧。我们假设，与标准氧疗（SOT）相比，高频硝化氧可改善 CAD 患者的 CCE。方法和分析 MEHIS（MostCare-Based Assessment of CCE in CAD Patients高频硝化氧治疗与镇静下 GIE 的标准氧治疗）是一项前瞻性的单中心随机研究。前瞻性单中心随机对照）研究是一项单中心随机对照试验，比较了在手术室由麻醉师对 CAD 患者进行深度镇静的 GIE 期间使用 HFNO 和 SOT 的效果。90 名患者将按 1:1 的比例随机分配到两个平行组。主要结果是两组患者在镇静期间的 CCE 水平差异。次要结果是低血压的发生率（低血压定义为收缩压低于 80 mmHg）、手术后 6-12 小时的 BNP（脑钠肽）、TnI（肌钙蛋白 I）和乳酸盐水平、低氧血症的发生率（SpO2 测量值等于或低于 92%）、不包括主要结果在内的大多数护理血液动力学参数、维持上气道通畅所需的干预措施、患者躁动发作（通过触摸供氧装置进行评估）以及术后是否出现术中不良记忆。关键词 高流量鼻氧疗法（HFNO）；心脏循环效率（CCE）；胃肠道内窥镜检查（GIE）；冠状动脉疾病（CAD 试验注册号：ChiCTR2400086887 本研究的优势和局限性 1.这是第一项比较 HFNO 和 SOT 为接受 GIE 的 CAD 患者吸氧的单中心随机实用性研究。2.2. 与通常在 SOT 中使用的高吸入氧饱和度（FiO2）的 HFNO 与低氧流量及由此导致的较低 FiO2 相比，本研究调整了气体流量，使两组患者的应用 FiO2 水平大致相同。这种方法旨在评估高频硝化氧是否能通过呼气末正压和/或死腔冲洗效应改善 CCE。3.在 SOT 组中，无法保证精确的 FiO2。因此，我们使用预先存在的算盘来达到最佳等效。4.4. 从技术上讲，在研究组中对执业医师和其他护理人员进行盲法是不可行的。不过，记录的主要结果测量数据打印出来后，可以让对治疗分配保密的评估人员延迟阅读。我们在患者研究中采用了盲法。5.对于未进行气管内机械通气的患者，由于呼吸系统的影响，多数护理数据的收集可能会出现轻微偏差。不过，我们的研究中两组患者都是在镇静状态下进行的，并且进行了纵向比较，因此将这种偏差的影响降至最低。6.有上/下消化道出血的 CAD 患者通常患有贫血。我们将 CAD 患者分为贫血组和非贫血组，并比较了两种供氧模式下的 CCE。这为进一步评估高频硝化氧对贫血患者的氧疗效果提供了依据。
{"title":"MostCare-Based Assessment of Cardiac cycle efficiency in Coronary Artery Disease Patientsï¼ High-flow nasal cannula versus standard oxygenation for gastrointestinal endoscopy with sedation. The prospective single-center randomised controlled MEHIS study protocol","authors":"F. Xie, M. Jin, T. Ma, X. Zhou, S. Wang","doi":"10.1101/2024.07.27.24311111","DOIUrl":"https://doi.org/10.1101/2024.07.27.24311111","url":null,"abstract":"Introduction During gastrointestinal endoscopy (GIE) procedures(upper/lower) performed under deep sedation, patients with coronary artery disease(CAD) have poorer tolerance, with higher incidence of hypotension and myocardial ischemia. Patients with CAD should particularly avoid hypoxemia caused by deep sedation and increased oxygen consumption caused by inadequate sedation. Recent data indicate that high-flow nasal oxygen therapy (HFNO) is recommended for preventing hypoxemia in high-risk patients. The data on cardiac cycle efficiency (CCE) from MostCare can be used to assess myocardial oxygen supply-demand balance in patients with CAD. HFNO may potentially improve myocardial oxygen supply during GIE under deep sedation. We hypothesize that compared to standard oxygen therapy (SOT), HFNO could improve CCE in patients with CAD. Methods and analysis The MEHIS (MostCare-Based Assessment of CCE in CAD PatientsHFNO versus SOT for GIE with sedation. The prospective single-center randomised controlled) study is a single-center randomized controlled trial comparing the effects of HFNO and SOT during GIE under deep sedation administered by anaesthesiologists in the procedure room in patients with CAD. Ninety patients will be randomly allocated in a 1:1 ratio to two parallel groups. The primary outcome is the difference in CCE levels between the two groups during sedation. Secondary outcomes are the incidence of hypotension(hypotension defined as a systolic blood pressure below 80 mmHg), values of BNP (brain natriuretic peptide), TnI (troponin I), and lactate levels at 6-12 hours post-operationthe occurrence of hypoxemia defined as SpO2 measurement equal to or below 92%, MostCare hemodynamic parameters excluding the primary outcome, interventions required to maintain upper airway patency, patient agitation episodes (assessed by touching the oxygen supply device), and presence of intraoperative adverse memories postoperatively. Keywords high-flow nasal oxygen therapy (HFNO); cardiac cycle efficiency (CCE); gastrointestinal endoscopy (GIE); coronary artery disease(CAD) Trial registration number ChiCTR2400086887 Strengths and limitations of this study 1. This is the first pragmatic randomized single-center study comparing HFNO to SOT for oxygenating patients with CAD undergoing GIE. 2. In contrast to comparing HFNO with high fraction of inspired oxygen (FiO2) typically used in SOT with low oxygen flow and consequently lower FiO2, this study adjusts gas flows to target roughly the same level of applied FiO2 in both groups. This approach aims to assess whether HFNO can improve CCE through positive end-expiratory pressure and/or dead space washout effects. 3. In SOT group, precise FiO2 cannot be guaranteed. That is why we utilized a pre-existing abacus to achieve the best equivalence. 4. Technically, blinding of practitioners and other nursing staff to the study groups is not feasible. However, the printout of recorded primary outcome measures is produced, allo","PeriodicalId":506788,"journal":{"name":"medRxiv","volume":"2 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141796536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-29DOI: 10.1101/2024.07.26.24311052
A. Gupta, A. K. Singh, V. Gupta
Tobacco consumption remains one of the leading preventable causes of morbidity and mortality worldwide. Tobacco use is a major public health concern despite widespread public health efforts and strict regulations. Within the framework of the NCEP ATP-III criteria, the goal of the study was to investigate the effects of tobacco consumption on metabolic risk factors in young adult males. This case-control study comprised of 50 male participants aged 18 to 30 years; 25 male tobacco chewers were assigned to the study group, and 25 males who did not chew tobacco (non-tobacco chewers) were assigned to the control group. Anthropometric and metabolic risk factors that were compared between the study and control groups included waist circumference (WC), blood glucose, serum level of triglycerides (TG) and total cholesterol (TC), Insulin resistance (IR) and the homeostatic model assessment (HOMA) index, which is a measure of IR. The results of the study demonstrated that compared to non-tobacco chewers, tobacco chewers had significantly higher glucose (p=0.026), TC (p=0.0013), insulin (p=0.015), and IR (p=0.027). However, there were no discernible variations in HDL, VLDL, and TG levels, or WC. Nine male tobacco chewers and eight male non-tobacco chewers from the respective groups exhibited metabolic risk based on the NCEP ATP-III criterion of three out of five risk factors. Thus, we draw the conclusion that while tobacco chewers' lipid profiles stayed similar, their TC, hyperglycaemia, hyperinsulinemia, and HOMA Index increased, making them more susceptible to the onset of metabolic syndrome.
{"title":"EFFECT OF TOBACCO CHEWING ON METABOLIC RISK FACTORS IN NORTH INDIAN ADULT MALES","authors":"A. Gupta, A. K. Singh, V. Gupta","doi":"10.1101/2024.07.26.24311052","DOIUrl":"https://doi.org/10.1101/2024.07.26.24311052","url":null,"abstract":"Tobacco consumption remains one of the leading preventable causes of morbidity and mortality worldwide. Tobacco use is a major public health concern despite widespread public health efforts and strict regulations. Within the framework of the NCEP ATP-III criteria, the goal of the study was to investigate the effects of tobacco consumption on metabolic risk factors in young adult males. This case-control study comprised of 50 male participants aged 18 to 30 years; 25 male tobacco chewers were assigned to the study group, and 25 males who did not chew tobacco (non-tobacco chewers) were assigned to the control group. Anthropometric and metabolic risk factors that were compared between the study and control groups included waist circumference (WC), blood glucose, serum level of triglycerides (TG) and total cholesterol (TC), Insulin resistance (IR) and the homeostatic model assessment (HOMA) index, which is a measure of IR. The results of the study demonstrated that compared to non-tobacco chewers, tobacco chewers had significantly higher glucose (p=0.026), TC (p=0.0013), insulin (p=0.015), and IR (p=0.027). However, there were no discernible variations in HDL, VLDL, and TG levels, or WC. Nine male tobacco chewers and eight male non-tobacco chewers from the respective groups exhibited metabolic risk based on the NCEP ATP-III criterion of three out of five risk factors. Thus, we draw the conclusion that while tobacco chewers' lipid profiles stayed similar, their TC, hyperglycaemia, hyperinsulinemia, and HOMA Index increased, making them more susceptible to the onset of metabolic syndrome.","PeriodicalId":506788,"journal":{"name":"medRxiv","volume":"8 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141796542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-29DOI: 10.1101/2024.07.28.24309665
Daniel Marbach, Jurriaan Brouer-Visser, Laura Brennan, Sabine Wilson, Iakov I Davydov, Nicolas Staedler, José Duarte, Iris Martinez Quetglas, Eveline Nüesch, Marta Cañamero, E. Chesne, George Au-Yeung, Erika Hamilton, Stephanie Lheureux, D. Richardson, Iben Spanggaard, Bruno Gomes, I. Franjkovic, M. DeMario, M. Kornacker, K. Lechner, ID ClinicalTrials.gov
Purpose: Bromodomain and extra-terminal domain (BET) inhibitors (BETi) have demonstrated epigenetic modulation capabilities, specifically in transcriptional repression of oncogenic pathways. Preclinical assays suggest that BETi potentially attenuates the PD1/PD-L1 immune checkpoint axis, supporting its combination with immunomodulatory agents. Patients and Methods: A Phase 1b clinical trial was conducted to elucidate the pharmacokinetic and pharmacodynamic profiles of the BET inhibitor RO6870810, as monotherapy and in combination with the PD-L1 antagonist atezolizumab, in patients with advanced ovarian carcinomas and triple-negative breast cancer (TNBC). Endpoints included maximum tolerated dosages, adverse event profiling, pharmacokinetic evaluations, and antitumor activity. Pharmacodynamic and immunomodulatory effects were assessed in tumor tissue (by immunohistochemistry and RNA-seq) and in peripheral blood (by flow cytometry and cytokine analysis). Results: The study was terminated prematurely due to a pronounced incidence of immune-related adverse effects in patients receiving combination of RO6870810 and atezolizumab. Anti-tumor activity was limited to 2 patients (5.6%) showing partial response. Although target engagement was confirmed by established BETi pharmacodynamic markers in both blood and tumor samples, BETi failed to markedly decrease tumor PD-L1 expression and had a suppressive effect on anti-tumor immunity. Immune effector activation in tumor tissue was solely observed with the atezolizumab combination, aligning with this checkpoint inhibitor's recognized biological effects. Conclusions: The combination of BET inhibitor RO6870810 with the checkpoint inhibitor atezolizumab presents an unfavorable risk-benefit profile for ovarian cancer and TNBC (triple-negative breast cancer) patients due to the increased risk of augmented or exaggerated immune reactions, without evidence for synergistic anti-tumor effects.
目的：溴结构域和末端外结构域（BET）抑制剂（BETi）具有表观遗传调节能力，特别是在抑制致癌通路的转录方面。临床前试验表明，BETi 有可能减弱 PD1/PD-L1 免疫检查点轴，从而支持其与免疫调节药物联合使用。患者与方法：进行了一项 1b 期临床试验，以阐明 BET 抑制剂 RO6870810 作为单药和与 PD-L1 拮抗剂 atezolizumab 联用治疗晚期卵巢癌和三阴性乳腺癌 (TNBC) 患者的药代动力学和药效学特征。研究终点包括最大耐受剂量、不良事件分析、药代动力学评估和抗肿瘤活性。在肿瘤组织（通过免疫组化和RNA-seq）和外周血（通过流式细胞术和细胞因子分析）中评估药效学和免疫调节作用。研究结果由于接受RO6870810和atezolizumab联合治疗的患者出现了明显的免疫相关不良反应，研究提前结束。抗肿瘤活性仅限于2名患者（5.6%）出现部分反应。虽然血液和肿瘤样本中的既定 BETi 药效学标记物证实了靶点参与，但 BETi 未能显著降低肿瘤 PD-L1 的表达，并对抗肿瘤免疫产生抑制作用。只有阿特珠单抗联合用药时才能观察到肿瘤组织中免疫效应因子的激活，这与这种检查点抑制剂公认的生物效应相一致。结论BET抑制剂RO6870810与检查点抑制剂atezolizumab联合用药对卵巢癌和TNBC（三阴性乳腺癌）患者的风险-获益情况不利，因为会增加免疫反应增强或夸大的风险，但没有证据表明会产生协同抗肿瘤效应。
{"title":"Immune Modulation in Solid Tumors: A Phase 1b Study of RO6870810 (BET Inhibitor) and Atezolizumab (PD-L1 Inhibitor)","authors":"Daniel Marbach, Jurriaan Brouer-Visser, Laura Brennan, Sabine Wilson, Iakov I Davydov, Nicolas Staedler, José Duarte, Iris Martinez Quetglas, Eveline Nüesch, Marta Cañamero, E. Chesne, George Au-Yeung, Erika Hamilton, Stephanie Lheureux, D. Richardson, Iben Spanggaard, Bruno Gomes, I. Franjkovic, M. DeMario, M. Kornacker, K. Lechner, ID ClinicalTrials.gov","doi":"10.1101/2024.07.28.24309665","DOIUrl":"https://doi.org/10.1101/2024.07.28.24309665","url":null,"abstract":"Purpose: Bromodomain and extra-terminal domain (BET) inhibitors (BETi) have demonstrated epigenetic modulation capabilities, specifically in transcriptional repression of oncogenic pathways. Preclinical assays suggest that BETi potentially attenuates the PD1/PD-L1 immune checkpoint axis, supporting its combination with immunomodulatory agents. Patients and Methods: A Phase 1b clinical trial was conducted to elucidate the pharmacokinetic and pharmacodynamic profiles of the BET inhibitor RO6870810, as monotherapy and in combination with the PD-L1 antagonist atezolizumab, in patients with advanced ovarian carcinomas and triple-negative breast cancer (TNBC). Endpoints included maximum tolerated dosages, adverse event profiling, pharmacokinetic evaluations, and antitumor activity. Pharmacodynamic and immunomodulatory effects were assessed in tumor tissue (by immunohistochemistry and RNA-seq) and in peripheral blood (by flow cytometry and cytokine analysis). Results: The study was terminated prematurely due to a pronounced incidence of immune-related adverse effects in patients receiving combination of RO6870810 and atezolizumab. Anti-tumor activity was limited to 2 patients (5.6%) showing partial response. Although target engagement was confirmed by established BETi pharmacodynamic markers in both blood and tumor samples, BETi failed to markedly decrease tumor PD-L1 expression and had a suppressive effect on anti-tumor immunity. Immune effector activation in tumor tissue was solely observed with the atezolizumab combination, aligning with this checkpoint inhibitor's recognized biological effects. Conclusions: The combination of BET inhibitor RO6870810 with the checkpoint inhibitor atezolizumab presents an unfavorable risk-benefit profile for ovarian cancer and TNBC (triple-negative breast cancer) patients due to the increased risk of augmented or exaggerated immune reactions, without evidence for synergistic anti-tumor effects.","PeriodicalId":506788,"journal":{"name":"medRxiv","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141796553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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